The relation between neurofilament expression and/or phosphorylation in the proximal versus distal components of the sensory peripheral neuraxis was studied and related to disorders in structure and function of the distal axon of streptozocin (STZ)-induced diabetic rats studied for 14 weeks. The ability of neurotrophin-3 (NT-3) to prevent abnormalities in neurofilament biology was also investigated. Compared with age-matched controls, neurofilament heavy (NF-H) (3.3-fold) and neurofilament medium (NF-M) (2.5-fold), but not neurofilament light (NF-L), subunits accumulated in the proximal axon of sensory neurons of the lumbar dorsal root ganglia (DRG) in untreated diabetic rats. Neurofilament accumulation was prevented by NT-3. Small- and large-diameter sensory neurons exhibited elevated levels of NF-H protein accumulation and phosphorylation in the DRG of untreated diabetic rats, levels that were ameliorated by NT-3. The sural nerve of untreated diabetic rats showed a 50% decrease in the levels of NF-H and NF-M, but not NF-L, subunits; NT-3 only partially normalized the defect in NF-M expression. These observations were associated with significant lowering of motor and sensory nerve conduction velocity but no alteration in the mean axonal diameter of myelinated axons in the sural nerve in untreated diabetic rats. It is proposed that the accumulation of NF-H and NF-M subunits in the proximal axon is an etiologic factor in the distal axon degeneration observed in diabetes.